Current Trends in Lactate Metabolism:

Introduction
L. BRUCE GLADDEN
Department of Kinesiology, Auburn University, Auburn, AL

ABSTRACT
GLADDEN, L. B. Current Trends in Lactate Metabolism: Introduction. Med. Sci. Sports Exerc., Vol. 40, No. 3, pp. 475–476, 2008. In
September 2006, at the Integrative Physiology of Exercise meeting in Indianapolis, IN, a symposium entitled ‘‘Current Trends in
Lactate Metabolism’’ was presented. This short paper introduces two papers from that symposium. The first paper by L. Bruce Gladden
briefly summarizes key pieces of evidence that support the cell-to-cell lactate shuttle, a concept that is no longer an hypothesis but that,
instead, is now an established theory that provides the context for discussions of whole body metabolism. Gladden also offers a critical
appraisal of the intracellular lactate shuttle and evaluates an ongoing controversy relative to the role of lactate in acid–base balance. In

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the second paper, Hashimoto and Brooks provide their evidence in support of the intracellular lactate shuttle and a lactate oxidation
complex in the inner mitochondrial membrane. They also postulate that lactate is a cell-signaling molecule, ‘‘lactormone,’’ that can
upregulate gene and protein expression. Both papers have been updated since their original presentations and represent the current
state of knowledge. Key Words: LACTATE HISTORY, LACTATE SHUTTLE, CELL-TO-CELL LACTATE SHUTTLE,
INTRACELLULAR LACTATE SHUTTLE, LACTATE OXIDATION COMPLEX, LACTIC ACIDOSIS

muscles are placed in O2-rich environments, Laj disap-

A
s detailed by Brooks and me (4) in an historical
review, the study of lactate (Laj) metabolism can
be divided into several important time periods or
eras. During the Pre-Lactate Era (~1780–1907), Scheele
discovered Laj in sour milk in 1780 (14), and in 1808
Berzelius reported an elevated concentration of Laj ([Laj])
in ‘‘the muscles of hunted stags’’ (18). Several other notable
studies were reported in the 1800s, including evidence that
activity caused muscles to become acidic and that the
amount of Laj increased with the amount of work done (4).
In 1907, the Lactate Era (1907–1926) was ushered in by
the classic studies of Fletcher and Hopkins (7). They (7)
developed a method to prevent significant Laj formation in
resting muscles before the extraction and analysis of the
Laj. Accordingly, they were able to demonstrate that 1)
freshly excised resting muscle contains only a small amount
of Laj, 2) [Laj] increases in excised, resting, anaerobic
muscles, 3) La j accumulates to high levels during
stimulation of muscles to fatigue, and 4) when fatigued
Editor’s Note: This paper is an Editor-in-Chief–invited contribution from
ACSM’s conference on Integrative Physiology of Exercise held in
Indianapolis, Indiana, September 27–30, 2006.
Address for correspondence: L. Bruce Gladden, Department of Kinesiol-
ogy, 2050 Memorial Coliseum, Auburn University, Auburn, AL 36849-
5323; E-mail: gladdlb@auburn.edu.
Submitted for publication June 2007.
Accepted for publication September 2007.
0195-9131/08/4003-0475/0
MEDICINE & SCIENCE IN SPORTS & EXERCISEÒ
Copyright Ó 2008 by the American College of Sports Medicine
DOI: 10.1249/MSS.0b013e31816154c9
pears. Subsequently, Laj took center stage with the work of
A.V. Hill (9) and the paradigm that Laj was the immediate
energy donor for muscle contraction.
A ‘‘revolution in muscle physiology’’ (10) occurred
between 1926 and 1932 with the discoveries of both
adenosine triphosphate (ATP) and phosphocreatine (PC);
this period could be called the Phosphagen Era. Based on
his own work and that of others, Lohmann (15–17)
postulated that ATP hydrolysis was the immediate source
of energy for muscle contraction and that PC was used to
resynthesize ATP in the creatine kinase reaction (1). Direct
evidence of ATP breakdown during contractions did not
become available until about 30 yr later. Credit for this
proof usually goes to Cain and Davies (5), who inhibited
creatine kinase in muscles with the poison 1,fluoro-2,4-
dinitrobenzene (FDNB) and then immediately froze the
muscles after a series of contractions. Under these con-
ditions in which ATP resynthesis from PC was prevented, a
decline in ATP concentration was observed. Notably, Lange
(13) had reported similar results 7 yr earlier. The reason for
the difficulty in obtaining absolute evidence of ATP
hydrolysis in muscle contractions is the incredibly rapid
kinetics of the creatine kinase reaction (1). Lardy`s group
(12) calculated that all of the ATP in a rabbit skeletal
muscle could be resynthesized from ADP and PC in only 30
ms (1), thus preventing detection of ATP breakdown unless
the creatine kinase reaction were blocked.
Given the association between Laj, O2, and fatigue
(dating from Fletcher and Hopkins (7) and A.V. Hill (9)),
and the removal of Laj from its eminent position as the
immediate energy donor for muscle contraction, it is no

475

Copyright @ 2008 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
 surprise that a long period following the 1930s could be
called the Dead-End Waste Product Era from the perspec-
tive of Laj metabolism. Certainly, there was a great deal of
research during this period including a flurry of activity
surrounding the ‘‘anaerobic threshold,’’ a term coined by
Wasserman and McIlroy (19) in 1964. In 1973, Wasserman,
his colleague Whipp, and other coworkers refined the concept
in their classic paper (20), which generated tremendous inter-
est in the topic. Although contrary evidence was beginning
to mount (6,11), in the minds of many, Laj was a detri-
mental by-product of high-intensity, O2-limited metabolism.
As recounted in the first of two papers in this symposium,
the prevailing view of Laj in metabolism underwent a sea
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476 Official Journal of the American College of Sports Medicine
Copyright @ 2008 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
change following the introduction of what is now known as
the cell-to-cell lactate shuttle by George Brooks in 1984 (2).
In terms of Laj metabolism, we are presently in the midst
of what could be called the Lactate Shuttle Era (8). In the
first symposium paper, I briefly summarize the overwhelm-
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shuttle (3), and analyze an ongoing debate about lactic
acidosis. In the second paper, Hashimoto and Brooks
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